Epidemiological and experimental evidence points to sex differences in the responses to antinociceptive pharmacological agents, the experience of pain, and the prevalence of certain chronic pain conditions, such as temporomandibular disorders (TMD). It has been suggested that these reflect the presence of sex-differences in brain neurochemical systems involved in pain perception and control, and that these may also be hormone-sensitive. The application of functional imaging techniques allows the direct examination of neuronal networks and neurochemical systems involved in the human experience of pain. The overall goal of the proposed research is the description and understanding of relevant aspects of the gender-specific neurobiology that occurs as the human undergoes tonic pain. The current proposal focuses on the opioid system, and specifically the mu opioid receptors, since these sites mediate many of the actions of exogenously administered antinociceptive drugs, as well as stress- and nociception-induced analgesia. Preliminary data using PET demonstrate that regions involved in the modulation of pain, such as the anterior cingulate cortex, prefrontal cortex, amygdala, thalamus and midbrain, show sex-differences in the concentration of mu opioid receptors. Additional findings reveal that the function of these receptors is subject to modulation by circulating estradiol, making this receptor site a logical candidate for the investigation of pain mechanisms and their differences between the sexes. This proposal takes advantage of state-of-the-art brain imaging technology for the quantification of mu opioid receptor sites in the human brain. It combines PET with a validated model of temporomandibular pain to examine the involvement of the mu opioid receptors in the regulation of tonic pain. A randomized, double blind, repeated measures crossover design will be employed to investigate the effect of tonic experimental pain on the opioid function of healthy subjects. The in vivo availability of 4 opioid receptors, as measured in living human subjects with PET and the selective radiotracer [11C]carfentanil will be quantified under baseline, placebo and tonic pain conditions. Baseline regional receptor levels, and receptor occupancy resulting from the administration of control and algesic substances into the masseter muscle, will be quantified. Regional binding and receptor occupancy will be related to psychophysical aspects of pain in men and women. These studies will show for the first time the function of the mu opioid receptor and the endogenous opioid system as the human undergoes pain. It will also examine the effect of sex and the involvement of various brain regions on sensory and affective components of pain.